Tubulocystic carcinoma of the kidney (TC-RCC) is a rare renal tumor and has been recently included as a distinct entity in WHO classification of renal neoplasms. We report the case of a patient with metastatic tubulocystic RCC whose disease progressed through standard of care treatment for nonclear RCC. However, genetic analysis revealed a germline pathogenic variant of fumarate hydratase (FH) gene, and the patient had a sustained and durable response to pazopanib.

© 2023 The Author(s). Published by S. Karger AG, Basel

Introduction

Renal cell carcinoma (RCC) accounts for 2% of all cancer diagnoses and cancer deaths worldwide [1, 2]. RCC is a heterogeneous group of cancers that can occur sporadically or as a manifestation of various inherited syndromes. Major subtypes include clear cell RCC, papillary RCC, and chromophobe RCC. The remaining subtypes are rare.

Tubulocystic carcinoma of the kidney (TC-RCC) is a rare renal tumor with unique gross and microscopic features [3–6]. Earlier, the tumors were thought to originate from the collecting ducts and exhibit indolent behavior with a low metastatic potential. The tumors exhibit a spongy or “bubble wrap” appearance reflecting the microscopic presence of variably sized cystically dilated tubules. The neoplastic cells have abundant eosinophilic cytoplasm and enlarged nuclei with prominent nucleoli. Immunohistochemistry and ultrastructural examination show features of proximal convoluted tubules and distal nephron [4]. Later, metastatic potential and aggressive clinical behavior of TC-RCC was reported [6]. Furthermore, there were reports suggesting that TC-RCC may even be closely related to papillary RCC [5]. However, comparative genomic microarray analysis has shown that tubulocystic carcinoma shows gains of chromosome 17, but not chromosome 7, whereas most papillary RCCs showed chromosomal gains in both chromosomes 7 and 17 [3].

Based on its unique pathological features, molecular signature, as well as the biological behavior, TC-RCC was included in the 2016 World Health Organization classification of tumors of the kidney as a distinct entity [7]. However, owing to the relative rarity of tumors and hence the lack of randomized trials for individual tumor types, all no clear cell RCC are grouped together and treated in a similar manner.

The treatment of metastatic RCC, including the nonclear cell type, has gone through rapid evolution in the last decade and consists mainly of immune checkpoint inhibitors, either in combination with another immune checkpoint inhibitor or with a tyrosine kinase inhibitor. Some excellent reviews summarizing the progress have been recently published [8–10].

Herein, we report the case of a patient with metastatic tubulocystic RCC whose disease progressed through standard of care treatment for nonclear RCC. However, genomic profiling revealed a therapeutic target in the form of mutant fumarate hydratase (FH) gene, and the patient had a sustained and durable response to pazopanib (offered as a third-line treatment). We discuss the clinical course of the patient and the molecular mechanisms underlying of the response. The CARE checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see www.karger.com/doi/10.1159/000528697).

Case Report

A 28-year-old gentleman underwent right radical nephrectomy in 2002 for pT3a N0M0 poorly differentiated right kidney neoplasm with a sarcomatoid change. He remained under surveillance until 2018. Past medical history was not significant for any illness. The patient smoked tobacco for 10 years without any history of alcohol intake or family history of cancer. He has 6 siblings and 5 children.

Sixteen years after the diagnosis of RCC, the patient presented with pain in the right shoulder, and an X-ray showed multiple lytic lesions in the head, the proximal diaphysis of the humerus, and glenoid process and coracoid process of the scapula, largest lesion measuring 3.7 cm × 3.5 cm. MRI of the right shoulder revealed multiple abnormal signal intensity expansile lesions in the scapula and in proximal third of the humerus (shown in Fig. 1a). A bone scan revealed multiple lesions (shown in Fig. 1b). A PET scan showed non-FDG avid pulmonary nodules, FDG avid paratracheal and left hilar pathological lymph nodes, and multiple skeletal lesions. An ultrasound-guided core biopsy from the right iliac bone soft tissue revealed the diagnosis of tubulocystic carcinoma of the kidney (shown in Fig. 2).

Fig. 1.

a MRI right shoulder: The lesion involving the scapula was reaching up to the glenoid and had a significant soft tissue component, which is abutting the posterior aspect of the subscapularis muscle and displacing it. The coracoid process of the scapula is also involved. The scapular lesion approximately measures about 47 × 36 mm and the humeral lesion measures approximately 20 × 18 mm. b Bone scan: uptake in right temporoparietal skull, right shoulder joint, right 3rd anterior rib, right femur involving trochanter, mid-shaft and distal femur, right distal tibia, right SI joint, and ischium bone.

Fig. 2.

a–d Core biopsy: section comprises multiple cores all containing a malignant tumor composed of closely packed acinar tubular and cystic structures lined by a single layer of larger cuboid cells with eosinophilic granular cytoplasm and hyperchromatic nuclei with prominent large nucleoli. Hobnailing nuclei were also seen. The mitoses 3–4/10 HPF and the stroma showed myxoid material. The tumor cells are positive for PAX8, AMACR, and vimentin and negative for PSA, RCC, CD10, Glypican 3, CD30, S100, CK7, CKHMWC, PANCK, CEA, and PLAP. Ki67 staining showed 25% of proliferative activity. The morphology and immunophenotype were consistent with tubulocystic carcinoma of kidney.

The case was discussed in the multidisciplinary tumor board and the patient was treated with palliative chemotherapy, consisting of 6 cycles of gemcitabine and cisplatin, complicated by dose-delaying cytopenias and dose reduction. The patient also received palliative radiotherapy to the right shoulder and underwent right prophylactic dynamic hip screw implantation, together with a retrograde femur nail and antegrade tibia nail.

Three months after the 6th dose of chemotherapy, PET scan showed a progressive disease. The patient was commenced on nivolumab 200 mg every 2 weeks. Toward the end of the 8th dose, the patient developed bilateral lower limb weakness, had inability to walk, and was found to have spasticity in both lower limbs and bilateral extensor plantars. MRI of the spine abnormal signal intensity mass lesions in multiple vertebral bodies involving D3, D4, L3, L5, and S2 vertebrae, and retropulsion of the posterior vertebral body element in the spinal canal, leading to significant cord compression (shown in Fig. 3a). MRI of the brain revealed a large well-defined right parieto-occipital extra-axial expansile calvarial soft tissue mass and an exuberant lesion in the left para median location near the vertex in the left parietal region. These lesions had a significant mass effect, leading to compression of the underlying brain parenchyma and perilesional dural enhancement (shown in Fig. 3b).

Fig. 3.

a MRI spine shows abnormal signal intensity mass lesions in multiple vertebral bodies involving D3, D4, L3, L5, and S2 vertebrae. The vertebra appears to be hyperintense on T2 and STIR sequences, and hypointense on T1-weighted sequences and showing post contrast enhancement and in keeping with vertebral body metastasis. Retropulsion of the posterior vertebral body element in the spinal canal at D4 level resulted in significant cord compression. Mild to moderate left lateral recess stenosis at L5-S1 level because of deposit in L5 vertebra. b MRI brain shows a large well-defined right parieto-occipital extra-axial expansile calvarial soft tissue mass measures about 65 × 62 mm. The lesion is low on T1-weighted and high on T2-weighted sequences and shows postcontrast enhancement.

The patient was deemed not fit for decompressive surgery for spinal cord compression because of the potential of high morbidity secondary to the vascularity of the tumor and the large size. The patient was referred for palliative radiotherapy to the calvarial metastases and to the D4 cord compression. The PET scan showed disease in multiple sites (shown in Fig. 4a).

Fig. 4.

a PET-CT showing widespread FDG avid metastasis to the right axillary/mediastinal lymph nodes, lungs, multiple skeletal, and left adrenal. b PET scan shows a partial response 10 months after treatment with pazopanib. (Although there is a small persistent right axillary lymph node, there is a significant reduction in the FDG-avid lesion in the left adrenal gland and multiple FDG avid skeletal lesions.) c, d Follow-up PET-CT at 15 and 21 months after commencing pazopanib, which shows a stable remission.

Molecular Tumor Board

The tissue specimen was sent for molecular analysis to CARIS Life Sciences Laboratory. The tumor tissue revealed a mutation in FH gene on exon 4 (c.425A>G), with an allele frequency of 97%, leading to the protein alteration (p.Q142R). PD-L1 expression on immunohistochemistry (using SP142) was negative (low staining intensity of 2+ in 3% of cells). Of the relevant biomarkers, it was not possible to calculate total mutational burden and microsatellite instability because the sequencing data did not reach minimum depth of coverage, and no mutation was detected on MET, PBRM1, SDHB, SDHC, SDHD, SETD2, TSC1, TSC2, and VHL genes, and no fusion was detected on NTRK1, NTRK2, and NTRK3, and RET using RNA sequencing.

Further Course of Action

The patient was commenced on pazopanib 800 mg od. Within a month, muscle power improved in the lower limb, and within 6 months, the patient started to mobilize. The mass over the scalp reduced in size significantly. The major side effect was the change in color of the skin and the hair, which both turned pale, and grade II neutropenia. A follow-up PET scan 10 months after commencing the treatment showed a reduction in the FDG-avid lesion in the left adrenal gland, and the right pelvic region anterior to the right iliac bone (shown in Fig. 4b). A follow-up PET scan 1 year after commencing pazopanib showed no evidence of a new FDG avid skeletal disease. Most of the previous FDG avid expansile skeletal lesions show mild to moderate increased in FDG uptake, a picture consistent with stable metabolic disease (shown in Fig. 4c). A further follow-up scan 1.5 years after commencing treatment with pazopanib showed stable metabolic disease (shown in Fig. 4d). At the time of writing, the patient remains well and is able to mobilize with support. The timelines of the main events of this case are displayed in Table 1.

Table 1.

Timelines of the main events of this case

Time from nephrectomy to systemic relapseFirst-line gemcitabine and cisplatinTreatment-free intervalSecond-line nivolumabSustained response to pazopanib16 years4 months3 months4 monthsMore than 30 monthsDiscussion

We describe the case of a young man diagnosed to have RCC, whose disease relapsed 16 years after nephrectomy. At the time of relapse, the disease was classified as TC-RCC. The metastatic disease progressed through two lines of treatment for nonclear RCC. Molecular profiling identified FH mutation as a possible therapeutic target, and the patient had a sustained response to the VEGFR-TKI, pazopanib.

The classification of RCC has evolved from a dichotomous “clear cell” and “granular cell” subtypes described in 1952, to the classification based on several morphological features, such as the architectural pattern (e.g., papillary RCC), the anatomical location (e.g., collecting duct RCC), and associated diseases (e.g., acquired cystic disease-associated RCC [7, 11]). Based on cytomorphology, the rare subtypes of RCC, such as renal medullary carcinomas, collecting duct carcinomas, and tubulocystic carcinomas, were classified together with hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome, which shared the common clinical features of being high grade and exhibiting aggressive clinical behavior [12].

HLRCC is an autosomal dominant hereditary cancer syndrome with incomplete penetrance. HLRCC arises as a result of germline mutation in FH gene [13]. Mutation in FH gene is classified as “likely pathogenic” and occurs because of a single nucleotide variant on chromosome 1q43. The c.425A>G variant leads to p.Gln142Arg, leading to loss of function of fumarate hydrogenase. FH has been included in the list of genomic “secondary findings” devised by the American College of Medical Genetics and Genomics (ACMG) in version 3.0, called ACMG73 [14]. HLRCC patients are genetically predisposed to develop skin leiomyomas, uterine fibroids, and the aggressive kidney cancer of type 2 papillary morphology. Loss of heterozygosity at the FH locus that causes a complete loss of FH enzymatic function is always detected in these tumor tissues [13].

More recently, RCC has been classified to more than 50 subtypes according to the molecular alterations, such as ALK rearrangement-associated RCC, MiT family translocation RCC, SDH-deficient RCC, or FH-deficient RCC. An emerging group of FH-deficient tumors has been reported [15, 16]. The term “FH-deficient RCC” is preferred over "hereditary leiomyomatosis and RCC syndrome-associated RCC" [17]. This may help not only to determine the prognosis better but also to guide to the most appropriate therapeutic path.

In FH-deficient RCC, oxidative phosphorylation is impaired, and aerobic glycolysis is upregulated. Energy production becomes almost fully dependent on glycolysis, which in turn promotes cell proliferation. The FH gene encodes for a protein called fumarate hydrogenase, which catalyzes the formation of L-malate from fumarate in the Kreb’s cycle. FH inactivation leads to accumulation of intracellular fumarate, which in turn leads to succinate accumulation, with consequent VHL-independent stabilization of hypoxia-inducible factor 1-α subunit, causing upregulation of vascular endothelial growth factor (VEGF) and glucose transporter 1, contributing to carcinogenesis [18]. Upregulation of VEGF and glucose transporter 1 is known to underlie the molecular mechanism of high-grade RCC [19]. Recently, gene expression patterns including angiogenic and immunogenic signatures generated from IMmotion 150 showed a strong correlation with response to immune checkpoint inhibitors and antiangiogenic agents, respectively. Our patient was treated with VEGFr-TKI, pazopanib and had a sustained response. The deep and sustained response to pazopanib observed in this patient suggests that FH-deficient patients with metastatic RCC or other tumors may be treated with TKIs. Whether other TKIs, such as sunitinib, axitinib, and cabozantinib, would also produce similar responses remains speculative. Further investigation of the transcriptomic features of this patient may further elucidate the molecular mechanism underlying the observed response and setting the stage for identification of more patients with potential response to this agent or other TKIs.

Conclusion

We report the case of a patient with metastatic RCC whose disease had been rapidly progressing through two lines of “standard” treatment, leading to severe complications and disability, and once the FH mutation was detected, the patient continues to have a sustained and durable remission, 2.5 years on pazopanib. To the best of our knowledge, a sustained response to pazopanib in FH-mutated Tc-RCC has not been reported. The case underscores the importance of comprehensive molecular profiling in cancer, especially the “rare” and the “difficult-to-treat” cancers.

Acknowledgments

Racha Aaraj, Pharm D, MSc, MPH from Phoenix Clinical Research, Lebanon, provided editorial assistance for the preparation of this manuscript. The authors thank the patient for accepting to publish the case.

Statement of Ethics

Ethical approval is not required for this case report in accordance with local or national guidelines. However, a written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

No funding was received in support of this case report.

Author Contributions

Dr. Anjum Othman, Dr. Shiyam Kumar, Dr. Asim Qureshi, Dr. Zabah Java, and Dr. Ikram A Burney were in charge of the medical care of the patient. They accepted responsibility for the medical care and the entire content of this submitted manuscript and approved submission.

Data Availability Statement

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.

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